Circulatory disorders caused by vascular system abnormalities are observed in numerous diseases, and specific examples of such diseases include angina pectoris, heart infarction, lower extremity circulatory failure caused by diabetes, and arterial occlusive disease. These diseases not only impart a great deal of pain to patients but also often lead patients to death. In order to overcome this problem, a great deal of research has been conducted regarding vascularization, and as a result, vascular endothelial growth factors (hereinafter abbreviated to “VEGF”) and their receptors (Flt-1, KDR) were found to play central roles therein (Ferara N. and Davis-Smyth T., Endocrine Review, 18, 4-25, 1997, Shibuya M., Advances in Cancer Research, 67, 281-316, 1995).
A possible method to ameliorate various circulatory failures is carried out by administering VEGF, an analogous protein thereof, or a vector for expressing them into subcutaneous tissue or muscular tissue of cardiac muscle or lower extremity to accelerate vascularization by these vascularization factors. Clinical experiments on VEGF have already started, and VEGF are known to bind to and activate both Flt-1 (VEGF receptor-1) and KDR (VEGF receptor-2) (Shibuya M. et al. Current Topics in Microbiology and Immunology, 237, 59-83, 1999). Approximately 90% of vascularization signals are sent from KDR (VEGF receptor-2) (Takahashi T. et al. Oncogene, 18, 2221-2230, 1999), while Flt-1 (VEGF receptor-1) sends out signals for the chemotaxis of monocytes and macrophages and relatively weak vascularization signals (Barleon B. et al. Blood, 87, 3336-3343, 1996, Clauss M. et al. Journal of Biological Chemistry, 271, 17629-17634, 1996). Monocytes and macrophage cells are known to secrete various cytokines and the like to induce inflammation, and are likely to disturb vascularization therapy. Accordingly, a VEGF analogous protein which binds to only KDR (VEGF receptor-2) and can activate it, is understood as more suitable for vascularization therapy. VEGF-ENZ-7 was reported as a protein that binds to only KDR (VEGF receptor-2) (Ogawa S. et al. Journal of Biological Chemistry, 273, 31273-31282, 1998). Although this gene per se was found in the Orf virus genome of Parapox in 1994, its property still remains unknown, and its characteristic features that it binds to only KDR (VEGF receptor-2) and has potent vascularization activity were elucidated for the first time by Ogawa et al. (Lyttle D. J. et al. Journal of Virology, 68, 84-92, 1994; Ogawa S. et al. Journal of Biological Chemistry, 273, 31273-31282, 1998).
Thereafter, VEGF-ED1701 and VEGF-ENZ-2, which are allied with VEGF-ENZ-7, were similarly reported as binding to only KDR (VEGF receptor-2) (FIG. 1) (Meyer M. et al. EMBO Journal 18, 363-374, 1999). As described above, VEGF-ENZ-7 binds to only KDR (VEGF receptor-2), has substantially the same vascularization activity as VEGF, and does not stimulate the chemotaxis of monocytes and macrophages.